Amyloidogenesis of SARS-CoV-2 Spike Protein

SARS-CoV-2 infection is associated with a surprising number of morbidities. Uncanny similarities with amyloid-disease associated blood coagulation andfibrinolytic disturbances together with neurologic and cardiac problems led us to investigatethe amyloidogenicity of the SARS-CoV-2 spike protein (S-protein). Amyloidfibril assays of peptide library mixtures and theoreticalpredictions identified seven amyloidogenic sequences within the S-protein. All seven peptides in isolation formed aggregates duringincubation at 37 degrees C. Three 20-amino acid long synthetic spike peptides (sequence 192-211, 601-620, 1166-1185) fulfilled threeamyloidfibril criteria: nucleation dependent polymerization kinetics by ThT, Congo red positivity, and ultrastructuralfibrillarmorphology. Full-length folded S-protein did not form amyloidfibrils, but amyloid-likefibrils with evident branching were formedduring 24 h of S-protein coincubation with the protease neutrophil elastase (NE)in vitro.NEefficiently cleaved S-protein, renderingexposure of amyloidogenic segments and accumulation of the amyloidogenic peptide 194-203, part of the most amyloidogenicsynthetic spike peptide. NE is overexpressed at inflamed sites of viral infection. Our data propose a molecular mechanism forpotential amyloidogenesis of SARS-CoV-2 S-protein in humans facilitated by endoproteolysis. The prospective of S-proteinamyloidogenesis in COVID-19 disease associated pathogenesis can be important in understanding the disease and long COVID-19.

Automated summary

SARS-CoV-2 infection is associated with various morbidities. The spike protein of SARS-CoV-2 shows similarities to amyloid-disease associated blood coagulation and fibrinolytic disturbances, as well as neurologic and cardiac problems. Through experiments, researchers identified seven amyloidogenic sequences within the spike protein, and found that synthetic spike peptides can form amyloid-like fibrils when co-incubated with the protease neutrophil elastase. These findings suggest a potential molecular mechanism for amyloidogenesis of SARS-CoV-2 spike protein, which may be important in understanding COVID-19 disease-associated pathogenesis.